In the absence of CD154, administration of interleukin-12 restores Th1 responses but not protective immunity to Schistosoma mansoni

James P Hewitson; Paul A Hamblin; Adrian P Mountford

doi:10.1128/IAI.00252-07

In the absence of CD154, administration of interleukin-12 restores Th1 responses but not protective immunity to Schistosoma mansoni

James P Hewitson, Paul A Hamblin, Adrian P Mountford

Research output: Contribution to journal › Article › peer-review

Abstract

The cytokine interplay during the development of protective immunity to the radiation-attenuated (RA) schistosome vaccine has been extensively characterized over recent years, yet the role of costimulatory molecules in the development of cell-mediated immunity is much less well understood. Here we demonstrate the importance of CD40/CD154 in vaccine-induced immunity, as CD154(-/-) mice exposed to RA schistosomes develop no protection to challenge infection. We showed that vaccinated CD154(-/-) mice have defective Th1-associated immune responses in the skin-draining lymph nodes and the lungs, with reduced or absent levels of interleukin-12p40 (IL-12p40), gamma interferon, and nitric oxide, but elevated levels of lung IL-4 and IL-5. The expression of major histocompatibility complex II (MHC-II) on antigen-presenting cells recovered from the lungs of vaccinated CD154(-/-) mice was also severely compromised. The administration of anti-CD40 monoclonal antibody (MAb) to CD154(-/-) mice did not reconstitute sustained Th1 responses in the lymph nodes or the lungs, nor did the MAb restore anti-parasite immunoglobulin G production or protective immunity. On the other hand, the administration of recombinant IL-12 (rIL-12) to CD154(-/-) mice shortly after vaccination caused elevated and sustained levels of Th1-associated cytokines, rescued MHC-II expression by lung CD11c(+) cells, and restored the appearance of inflammatory effector foci in the lungs. However, the treatment of CD154(-/-) mice with rIL-12 did not restore protection. We conclude that protective immunity to the RA schistosome vaccine is CD154 dependent but is independent of IL-12-orchestrated cellular immune mechanisms in the lungs.

Original language	English
Pages (from-to)	3539-3547
Number of pages	9
Journal	Infection and Immunity
Volume	75
Issue number	7
DOIs	https://doi.org/10.1128/IAI.00252-07
Publication status	Published - Jul 2007

Bibliographical note

Copyright © 2007 by the American Society for Microbiology. This is an author produced version of a paper subsequently published in Infection and Immunity. Uploaded in accordance with the publisher's self-archiving policy.

Keywords

LEISHMANIA-MAJOR INFECTION
VACCINE-INDUCED IMMUNITY
DEFICIENT MICE REVEAL
DRAINING LYMPH-NODES
T-CELL-ACTIVATION
DENDRITIC CELLS
CD40 LIGAND
NITRIC-OXIDE
IFN-GAMMA
CD40/CD154 INTERACTIONS

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@article{0f1332da545640b8915eddcf23cf429a,

title = "In the absence of CD154, administration of interleukin-12 restores Th1 responses but not protective immunity to Schistosoma mansoni",

abstract = "The cytokine interplay during the development of protective immunity to the radiation-attenuated (RA) schistosome vaccine has been extensively characterized over recent years, yet the role of costimulatory molecules in the development of cell-mediated immunity is much less well understood. Here we demonstrate the importance of CD40/CD154 in vaccine-induced immunity, as CD154(-/-) mice exposed to RA schistosomes develop no protection to challenge infection. We showed that vaccinated CD154(-/-) mice have defective Th1-associated immune responses in the skin-draining lymph nodes and the lungs, with reduced or absent levels of interleukin-12p40 (IL-12p40), gamma interferon, and nitric oxide, but elevated levels of lung IL-4 and IL-5. The expression of major histocompatibility complex II (MHC-II) on antigen-presenting cells recovered from the lungs of vaccinated CD154(-/-) mice was also severely compromised. The administration of anti-CD40 monoclonal antibody (MAb) to CD154(-/-) mice did not reconstitute sustained Th1 responses in the lymph nodes or the lungs, nor did the MAb restore anti-parasite immunoglobulin G production or protective immunity. On the other hand, the administration of recombinant IL-12 (rIL-12) to CD154(-/-) mice shortly after vaccination caused elevated and sustained levels of Th1-associated cytokines, rescued MHC-II expression by lung CD11c(+) cells, and restored the appearance of inflammatory effector foci in the lungs. However, the treatment of CD154(-/-) mice with rIL-12 did not restore protection. We conclude that protective immunity to the RA schistosome vaccine is CD154 dependent but is independent of IL-12-orchestrated cellular immune mechanisms in the lungs.",

keywords = "LEISHMANIA-MAJOR INFECTION, VACCINE-INDUCED IMMUNITY, DEFICIENT MICE REVEAL, DRAINING LYMPH-NODES, T-CELL-ACTIVATION, DENDRITIC CELLS, CD40 LIGAND, NITRIC-OXIDE, IFN-GAMMA, CD40/CD154 INTERACTIONS",

author = "Hewitson, {James P} and Hamblin, {Paul A} and Mountford, {Adrian P}",

note = "Copyright {\textcopyright} 2007 by the American Society for Microbiology. This is an author produced version of a paper subsequently published in Infection and Immunity. Uploaded in accordance with the publisher's self-archiving policy.",

year = "2007",

month = jul,

doi = "10.1128/IAI.00252-07",

language = "English",

volume = "75",

pages = "3539--3547",

journal = "Infection and Immunity",

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T1 - In the absence of CD154, administration of interleukin-12 restores Th1 responses but not protective immunity to Schistosoma mansoni

AU - Hewitson, James P

AU - Hamblin, Paul A

AU - Mountford, Adrian P

N1 - Copyright © 2007 by the American Society for Microbiology. This is an author produced version of a paper subsequently published in Infection and Immunity. Uploaded in accordance with the publisher's self-archiving policy.

PY - 2007/7

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N2 - The cytokine interplay during the development of protective immunity to the radiation-attenuated (RA) schistosome vaccine has been extensively characterized over recent years, yet the role of costimulatory molecules in the development of cell-mediated immunity is much less well understood. Here we demonstrate the importance of CD40/CD154 in vaccine-induced immunity, as CD154(-/-) mice exposed to RA schistosomes develop no protection to challenge infection. We showed that vaccinated CD154(-/-) mice have defective Th1-associated immune responses in the skin-draining lymph nodes and the lungs, with reduced or absent levels of interleukin-12p40 (IL-12p40), gamma interferon, and nitric oxide, but elevated levels of lung IL-4 and IL-5. The expression of major histocompatibility complex II (MHC-II) on antigen-presenting cells recovered from the lungs of vaccinated CD154(-/-) mice was also severely compromised. The administration of anti-CD40 monoclonal antibody (MAb) to CD154(-/-) mice did not reconstitute sustained Th1 responses in the lymph nodes or the lungs, nor did the MAb restore anti-parasite immunoglobulin G production or protective immunity. On the other hand, the administration of recombinant IL-12 (rIL-12) to CD154(-/-) mice shortly after vaccination caused elevated and sustained levels of Th1-associated cytokines, rescued MHC-II expression by lung CD11c(+) cells, and restored the appearance of inflammatory effector foci in the lungs. However, the treatment of CD154(-/-) mice with rIL-12 did not restore protection. We conclude that protective immunity to the RA schistosome vaccine is CD154 dependent but is independent of IL-12-orchestrated cellular immune mechanisms in the lungs.

AB - The cytokine interplay during the development of protective immunity to the radiation-attenuated (RA) schistosome vaccine has been extensively characterized over recent years, yet the role of costimulatory molecules in the development of cell-mediated immunity is much less well understood. Here we demonstrate the importance of CD40/CD154 in vaccine-induced immunity, as CD154(-/-) mice exposed to RA schistosomes develop no protection to challenge infection. We showed that vaccinated CD154(-/-) mice have defective Th1-associated immune responses in the skin-draining lymph nodes and the lungs, with reduced or absent levels of interleukin-12p40 (IL-12p40), gamma interferon, and nitric oxide, but elevated levels of lung IL-4 and IL-5. The expression of major histocompatibility complex II (MHC-II) on antigen-presenting cells recovered from the lungs of vaccinated CD154(-/-) mice was also severely compromised. The administration of anti-CD40 monoclonal antibody (MAb) to CD154(-/-) mice did not reconstitute sustained Th1 responses in the lymph nodes or the lungs, nor did the MAb restore anti-parasite immunoglobulin G production or protective immunity. On the other hand, the administration of recombinant IL-12 (rIL-12) to CD154(-/-) mice shortly after vaccination caused elevated and sustained levels of Th1-associated cytokines, rescued MHC-II expression by lung CD11c(+) cells, and restored the appearance of inflammatory effector foci in the lungs. However, the treatment of CD154(-/-) mice with rIL-12 did not restore protection. We conclude that protective immunity to the RA schistosome vaccine is CD154 dependent but is independent of IL-12-orchestrated cellular immune mechanisms in the lungs.

KW - LEISHMANIA-MAJOR INFECTION

KW - VACCINE-INDUCED IMMUNITY

KW - DEFICIENT MICE REVEAL

KW - DRAINING LYMPH-NODES

KW - T-CELL-ACTIVATION

KW - DENDRITIC CELLS

KW - CD40 LIGAND

KW - NITRIC-OXIDE

KW - IFN-GAMMA

KW - CD40/CD154 INTERACTIONS

U2 - 10.1128/IAI.00252-07

DO - 10.1128/IAI.00252-07

M3 - Article

C2 - 17485453

SN - 1098-5522

VL - 75

SP - 3539

EP - 3547

JO - Infection and Immunity

JF - Infection and Immunity

IS - 7

ER -